During the current reporting period we did not perform any genotyping or analysis in the rheumatoid arthritis project. Genotyping and analysis for two other genetically complex disorders, Behcets disease and systemic onset juvenile idiopathic arthritis, were quite active, and are described in separate Z01 reports (HG200374-03 MGB and HG200370-03 MGB, respectively). We have begun a major new initiative to study the genetics of scleroderma in the African-American population. Scleroderma is an autoimmune disorder that is characterized by thickening and fibrosis of the skin, with systemic manifestations that can include renal involvement with accelerated hypertension, pulmonary involvement manifesting with either pulmonary fibrosis or pulmonary arterial hypertension, gastrointestinal involvement with esophageal dysmotility, and cardiac involvement with various electrical conduction defects. Scleroderma remains one of the greatest challenges in clinical rheumatology, and although the advent of angiotensin converting enzyme inhibitors has had a major impact on scleroderma renal disease, treatment options for the involvement of other organs, particularly the lungs, are limited. Like many other autoimmune diseases, scleroderma does not usually present with a Mendelian pattern of inheritance, but the risk of developing scleroderma is greater for someone with an affected relative than for someone in the general population. Genome-wide association studies have been conducted in Caucasians, identifying a number of susceptibility loci that are shared with other autoimmune diseases. The rationale for studying the genetics of scleroderma in the African-American population is that the disease appears to be more frequent and more severe among African-Americans than among the Caucasian population. It is therefore possible that genetic studies of scleroderma in African-Americans will uncover heretofore unrecognized genes and pathways contributing to the pathogenesis of this illness. During the current reporting period we have worked with Drs. Fred Wigley and Francesco Boin of Johns Hopkins University School of Medicine to develop a consortium of centers around the U.S. to collect samples from extremely well-phenotyped African-American scleroderma patients. On November 8, 2012, immediately before the annual meeting of the American College of Rheumatology, which was held in Washington, D.C., we hosted a meeting of investigators interested in participating in this endeavor, which we have named Genome Research in African-American Scleroderma Patients (GRASP). Participants included Drs. Boin and Wigley from Johns Hopkins, Dr. Virginia Steen from Georgetown, Dr. Maureen Mayes from the University of Texas at Houston, Dr. Rick Silver from the Medical University of South Carolina, Dr. Tom Medsger from the University of Pittsburgh, Dr. John Varga from Northwestern University, Dr. Barri Fessler from the University of Alabama at Birmingham, and Dr. Dan Furst from the University of California Los Angeles. At the November, 2012 meeting the group agreed to work together to collect phenotypic information and DNA specimens on what is hoped to be a cohort of approximately 1000 African-American patients with scleroderma. During the first phase of this study, there will be 3 major goals: 1) performing whole-exome analysis in rare multiplex African-American families with scleroderma; 2) performing deep resequencing of approximately 100 selected candidate genes in a discovery cohort of 400 African-American scleroderma patients, in order to identify possible rare variants associated with scleroderma in this population. These variants will be added to a custom Illumina genotyping chip that also interrogates rare and low-frequency coding variants identified through the 1000 Genomes project, and the custom chips will be used to genotype the entire population of African-American patients collected and a matched set of controls; 3) performing a genome-wide association study using a chip that provides maximal coverage of variants in the African and African-American populations. In a second phase of the study, which will probably commence 2 to 3 years from now, we aim to use next-gen sequencing strategies to identify scleroderma susceptibility loci. As it is currently conceived, all of the GRASP genotyping and sequencing will be done in the Inflammatory Disease Section of the NHGRI. Current progress on GRASP includes the following: 1) centers are now getting appropriate IRB approvals for sample collection; 2) Dr. Pravitt Gourh, a NIAMS Rheumatology fellow with extensive background in scleroderma, will be working on GRASP as his major project; 3) we have established a collaboration with Dr. Charles Rotimi of NHGRI, a world expert on genetics in African and African-American populations, to obtain appropriate control samples and in silico genotyping data; 4) we have placed a purchase order and paid for over 2000 custom Illumina chips to do the rare-variant genotyping; 5) the Scleroderma Research Foundation has pledged support to GRASP investigators to help defray the costs of sample collection. We expect that samples will begin arriving at in the Inflammatory Disease Section of NHGRI during the upcoming reporting period, and that we will commence deep resequencing in the discovery phase of the rare variants project.